Arosio Beatrice, Segat Ludovica, Milanese Michele, Galimberti Lorenza, Calabresi Carmen, Zanetti Mariella, Trabattoni Daria, Annoni Giorgio, Crovella Sergio, Vergani Carlo
Geriatric Unit, Department of Internal Medicine, University of Milan, Ospedale Maggiore Policlinico, IRCCS Milano, Via Pace 9, Milan, Italy.
Aging Clin Exp Res. 2007 Oct;19(5):406-9. doi: 10.1007/BF03324722.
Peptydil prolyl cis-trans isomerase (PIN-1), which specifically regulates the conformational changes following phosphorylation of several proteins, targets the inactive hyper-phosphorylated tau on the Thr231-Pro motif and directly restores its biological function. Interestingly, PIN-1 is oxidatively inhibited not only in Alzheimer's disease brain but also in the hippocampi of mild cognitive impairment (MCI) subjects. The PIN-1 gene is characterized by two single nucleotide polymorphisms (SNPs) in the promoter region which are associated with the risk of Alzheimer's disease. The aim of this study was to analyse the genotype and allele distributions of these PIN-1 SNPs in MCI subjects diagnosed respectively as amnestic MCI (a-MCI) and multiple impaired cognitive domains (mcd-MCI) on the basis of cognitive features.
-667 T/C and -842 C/G SNPs were genotyped by polymerase chain reaction (PCR) amplification and direct sequencing in 43 MCI subjects, with the intention of comparing -667 and -842 SNP frequencies with those previously described in 111 Alzheimer's disease patients (AD) and 73 healthy controls (HC).
The allele frequencies of the -842 C/G SNP in a-MCI subjects are similar to those of AD subjects, while those of mcd-MCI are comparable to HC (G allele 83% in both a-MCI and AD; 95% and 94% in mcd-MCI and HC, respectively). A similar trend is also observed in -842 C/G genotypes.
Since a-MCI is thought to be the preclinical form of AD, the similar genotype distribution of -842 SNP in AD and a-MCI, but not in mcd-MCI, suggests that it is potentially involved in the conversion of a-MCI to AD. In conclusion, these findings support the theory that polymorphisms of the PIN-1 gene can affect neurodegeneration and its clinical progression.
肽基脯氨酰顺反异构酶（PIN-1）特异性调节多种蛋白质磷酸化后的构象变化，作用于苏氨酸231-脯氨酸基序上无活性的过度磷酸化tau蛋白，并直接恢复其生物学功能。有趣的是，PIN-1不仅在阿尔茨海默病患者大脑中受到氧化抑制，在轻度认知障碍（MCI）患者的海马体中也受到抑制。PIN-1基因的启动子区域有两个单核苷酸多态性（SNP），与患阿尔茨海默病的风险相关。本研究旨在分析基于认知特征分别诊断为遗忘型MCI（a-MCI）和多认知域受损型（mcd-MCI）的MCI患者中这些PIN-1 SNP的基因型和等位基因分布。
采用聚合酶链反应（PCR）扩增和直接测序技术对43例MCI患者的-667 T/C和-842 C/G SNP进行基因分型，旨在将-667和-842 SNP频率与先前在111例阿尔茨海默病患者（AD）和73例健康对照者（HC）中描述的频率进行比较。
a-MCI患者中-842 C/G SNP的等位基因频率与AD患者相似，而mcd-MCI患者的等位基因频率与HC相当（a-MCI和AD中的G等位基因频率均为83%；mcd-MCI和HC中分别为95%和94%）。在-842 C/G基因型中也观察到类似趋势。
由于a-MCI被认为是AD的临床前期形式，AD和a-MCI中-842 SNP的基因型分布相似，而在mcd-MCI中则不同，这表明它可能参与了a-MCI向AD的转化。总之，这些发现支持PIN-1基因多态性可影响神经退行性变及其临床进展这一理论。
